Exposure to radionuclides may have different origins, from the involvement of a nuclear worker after breaking of the containment of a glove box for example, to that of a multitude of people contaminated by the widespread dissemination of radionuclides in the environment: incident/accident or natural disaster affecting facilities of research, production, operation or storage of nuclear materials, military conflict with nuclear weapons, radionuclide containing weapons, terrorist act aiming at these facilities or characterized by an explosive device dispersing radionuclides called “dirty bomb.”
Internalized radionuclides are highly toxic and may cause both acute and chronic radiation injuries. The nuclides the most frequently encountered in these scenarios include americium, cesium, iodine, plutonium, strontium, uranium. Plutonium (Pu) is an example of highly toxic transuranic actinide alpha emitter. Once internalized in the body, Pu is overwhelmingly and efficiently distributed between the primary site of infection (e.g. the lungs in the case of inhalation) and the two main secondary tissue deposits (bone and liver), for very long periods.
To reduce the cumulative radiation dose delivered to the tissues by the Pu atoms, and thus reduce the risk of developing diseases, the only possibility is their decorporation by chelation to facilitate their excretion by natural means.
Currently, the only recommended treatment for actinide/lanthanide decorporation, such as Pu decorporation, is chelator diethylene triaminopentaacetic acid (DTPA), which in its dosage form solution benefits from a marketing authorization in France (2008), Germany (2005) and the approval of the Food and Drug Administration USA (2004). The marketed DTPA solution can be injected or infused intravenously, applied on a contaminated wound, or nebulized for inhalation.
DTPA is highly polar at neutral pH and is thus poorly (<10%) or variably absorbed when delivered orally. Consequently, DTPA is generally administered through more invasive routes, such as intravenous injection for internal contamination routes. Intravenous administration requires medical assistance and can thus not be autonomously used by any contaminated person.
Nebulization administration and flush of a contaminated wound are local and not optimal administration routes for decorporation efficacy in patients and do not necessarily afford systemic delivery. Wound flushing with a solution comprising DTPA triggers spilling of contaminated DTPA solution and waste of a great quantity of DTPA.
Reddy et al. Drug Development Research 2012, 73, 232-242 and US 2013/0251815 disclose enteric-coated gelatin capsules encapsulating DTPA that are safe and capable of decorporating actinides. Said capsules can be administered orally.
Jay et al. U.S. Pat. No. 8,030,358 and WO 2013/109323 disclose oral and topical delivery of DTPA prodrug formulations respectively.
However, there still exists a real need of new formulations, which would allow simple and autonomous (i.e. without medical assistance) administration of decorporating agents, such as DTPA. Such formulations would be especially appropriate for large-scale treatment of contaminated people and chronic treatments. In addition, most described systems for oral or local delivery require the use of high doses of DTPA, because these routes do not favor the uptake of the active agent.
Metal poisoning is a serious health problem. It can occur in different contexts, and potentially involves a wide variety of metals. Metal can also be present in too high
U.S. Pat. No. 5,494,935 discloses the use of compositions comprising partially lipophilic polyaminocarboxylic acids, for chelating heavy metals in specific organs in the body. These compositions are in particular capable of oral administration.
The described formulations for oral delivery of decontaminating agents or of agents for treating metal intoxication often require high doses, may be toxic and are usually not as efficient as the corresponding formulations for intravenous administration.
WO 2011/117333 discloses the use of a reverse-micellar system based on acylglycerols, phospholipids or sphingolipids and metal ions. Said reverse micellar systems are able to cross mucosa and cellular membranes and thus allow vectorization of metal ions to target sites. The reverse-micellar system allows the delivery of the metal ions to many different organs.
The Applicant surprisingly evidenced that reverse-micellar systems based on acylglycerols, sterols, lecithin, ethanol, water and a chelating or sequestering agent are appropriate for efficient chelation of radionuclides and/or metals in the whole body. Said reverse-micellar system can be advantageously delivered by transmucosal route, and favour the delivery and/or absorption of the active agent into the desired cells or organs. The reverse-micellar system acts both as a protecting shell around the active agent, and as a vector for its delivery to the desired cells and/or organs.